Stimulus sensitive gel with radioisotope and methods of making

Abstract

The present invention is a thermally reversible stimulus-sensitive gel or gelling copolymer radioisotope carrier that is a linear random copolymer of an [meth-]acrylamide derivative and a hydrophilic comonomer, wherein the linear random copolymer is in the form of a plurality of linear chains having a plurality of molecular weights greater than or equal to a minimum gelling molecular weight cutoff. Addition of a biodegradable backbone and/or a therapeutic agent imparts further utility. The method of the present invention for making a thermally reversible stimulus-sensitive gelling copolymer radionuclcide carrier has the steps of: (a) mixing a stimulus-sensitive reversible gelling copolymer with an aqueous solvent as a stimulus-sensitive reversible gelling solution; and (b) mixing a radioisotope with said stimulus-sensitive reversible gelling solution as said radioisotope carrier. The gel is enhanced by either combining it with a biodegradable backbone and/or a therapeutic agent in a gelling solution made by mixing the copolymer with an aqueous solvent.

1. A radioisotope carrier, comprising:
 (a) a stimulus-sensitive methacrylamide gelling polymer in an aqueous solution which gelling polymer changes from a first fluent state to a second, less fluent state upon exposure to an increase in temperature, a change in ionic strength, and/or a change in pH, wherein the gelling polymer remains in the second, less fluent state upon dilution; and  
 (b) an aqueous insoluble or confined radioisotope mixed with said gelling polymer as said radioisotope carrier.  
 
     
     
       2. A radioisotope carrier comprising:
 a gelling copolymer comprising 
 (a) a linear random copolymer in an aqueous solvent, having 
 (i) an [meth-]acrylamide derivative; and.  
 (ii) a hydrophilic comonomer; said linear random copolymer in the form of a plurality of linear chains having a plurality of molecular weights greater than or equal to a minimum gelling molecular weight cutoff;  
 
 (b) the aqueous solvent mixed with said linear random copolymer as a reversible gelling solution; and  
 (c) an aqueous insoluble or confined radioisotope mixed with said gelling copolymer as said radioisotope carrier.  
 
 
     
     
       3. The radioisotope carrier as recited in  claim 2 , wherein an amount of said hydrophilic comonomer in the linear random copolymer is less than about 10 mole %. 
     
     
       4. The radioisotope carrier as recited in  claim 3 , wherein said amount is about 2 mole %. 
     
     
       5. The radioisotope carrier as recited in  claim 2 , wherein said [meth-]acrylamide derivative is an N,N′-alkyl substituted [meth-]acrylalmide. 
     
     
       6. The radioisotope carrier as recited in  claim 5 , wherein said N,N′-alkyl substituted [meth-]acrylamide is selected from the group consisting of N-isopropyl[meth-]acrylamide, N,N′-diethyl[meth-]acrylamide, N-[meth-]acryloylpyrrolidine, N-ethyl[meth-]acrylalmide, and combinations thereof. 
     
     
       7. The radioisotope carrier as recited in  claim 2 , wherein said hydrophilic comonomer is hydrophilic [meth]acryl-compound. 
     
     
       8. The radioisotope carrier as recited in  claim 7 , wherein said hydrophilic [meth-]acryl-compound is selected from the group consisting of [meth-]acrylamide, hydrophilic [meth-]acrylic acid ester, hydrophilic [meth-]acrylamide derivatives and combinations thereof. 
     
     
       9. The radioisotope carrier as recited in  claim 8 , wherein said hydrophilic [meth-]acrylamide derivatives are selected from the group consisting of N,N-diethyl[meth-]acrylamide,2-[N,N-dimethylamino]ethyl[meth-]acrylamide, 2-[N,N-diethylamino]ethyl[meth-]acrylamide, or combinations thereof. 
     
     
       10. The radioisotope carrier as recited in  claim 8 , wherein said hydrophilic [meth-]acrylic ester is selected from the group consisting of 2-[N,N-diethylamino]ethyl[meth-]acrylate, 2-[N,N-dimethylamino]ethyl[meth-]acrylate, and combinations thereof. 
     
     
       11. The radioisotope as carrier as recited in  claim 2 , wherein said aqueous solvent is selected from the group consisting of water, and aqueous salt solution. 
     
     
       12. The radioisotope carrier as recited in  claim 11 , wherein said salt solution is a phosphate buffered saline. 
     
     
       13. The radioisotope carrier as recited in  claim 12 , wherein an amount of said solvent is from about 70 wt % to about 99 wt %. 
     
     
       14. The radioisotope carrier as recited in  claim 1 , wherein said radioisotope is selected from the group consisting of yttrium-90, indium-111, radium-223, actinium-225, bismuth-212, bismuth-213, scandium-47, astatine-211, rhenium-186, rhenium-188, iodine-131, iodine-124, lutetium-177, holinium-166, ˜amarium-153, copper-64, copper-67, phosphorus-32 and combinations thereof. 
     
     
       15. The radioisotope carrier as recited in  claim 1 , wherein said confined radioisotope is selected from the group of chelators, capsules and combinations thereof. 
     
     
       16. The radioisotope carrier as recited in  claim 15 , wherein said chelators are selected from the group consisting of 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA), tetra-butyl-calix[4]arene-crown-6-dicarboxylic acid (TBBCDA), 5,11,17,23-tetra-t-butyl-25,26,27,28-tetrakis (carboxymethoxy)-calix[6]arene (HBHC), diethylenetriamine-pentaacetic acid (DTPA), EDTA, and combinations thereof. 
     
     
       17. The radioisotope carrier as recited in  claim 15 , wherein said capsules are selected from the group of glass beads, polymer beads and combinations thereof. 
     
     
       18. The radioisotope carrier as recited in  claim 1 , further comprising a contrast agent. 
     
     
       19. The radioisotope carrier as recited in  claim 18 , wherein said contrast agent is selected from the group of gamma-emitting radioisotope, ultrasound contrast enhancing agent, paramagnetic isotope, positron-emitting radioisotope and combinations thereof. 
     
     
       20. The radioisotope carrier as recited in  claim 19 , wherein said gamma-emitting radioisotope is selected from the group of Tc-99m, In-111, Rh-186, Rh-188, Th-201, Ga-67, Y-86, Y-91, I-131, F-18, Cu-64, Cu-67, As-74, Zr-89 and combinations thereof. 
     
     
       21. The radioisotope carrier as recited in  claim 19 , wherein said ultrasound contrast enhancing agent is a plurality of air-filled albumin-coated microspheres, human serum albumin with octofluoropropane. 
     
     
       22. The radioisotope carrier as recited in  claim 19 , wherein said paramagnetic isotope is gadolinium. 
     
     
       23. The radioisotope carrier as recited in  claim 22 , wherein said gadolinium is a chelate selected from the group consisting of gadolinium-DTPA, gadolinium-EDTA and combinations thereof. 
     
     
       24. A radioisotope carrier, comprising:
 (a) a reversible stimulus-sensitive methacrylamide gelling polymer in an aqueous solution which gelling polymer changes from a liquid state to a gel state upon exposure to a change in temperature, ionic strength, sheer stress, and/or in pH, wherein the gelling polymer is in a liquid state at temperatures in a range of from about 20° C. to about 30° C.; and  
 (b) an aqueous insoluble or confined radioisotope mixed with said gelling polymer as said radioisotope carrier.  
 
     
     
       25. A radioisotope carrier, comprising:
 (a) a reversible stimulus-sensitive methacrylamide gelling polymer in an aqueous solution which gelling polymer changes from a first fluent state to a second, less fluent state upon exposure to a specific stimulus comprising a change in temperature, ionic strength, sheer stress, and/or pH, wherein the gelling polymer reverses from the second, less fluent state to the first fluent state only when the specific stimulus is reversed; and  
 (b) an aqueous insoluble or confined radioisotope mixed with said gelling polymer as said radioisotope carrier.